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Review
. 2017 May 26;6(6):e004918.
doi: 10.1161/JAHA.116.004918.

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Ci Song  1   2 , Stephen Burgess  3 , John D Eicher  4   2 , Christopher J O'Donnell  4   5 , Andrew D Johnson  4   2
Affiliations
Review

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Ci Song et al. J Am Heart Assoc. .

Abstract

Background: Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk.

Methods and results: To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol.

Conclusions: Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.

Keywords: Mendelian randomization; coronary heart disease; genome‐wide association study; plasminogen activator inhibitor type 1; single nucleotide polymorphism.

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Figures

Figure 1
Figure 1
Flow chart for article selection in systematic meta‐analysis. CHD indicates coronary heart disease.
Figure 2
Figure 2
Observational associations of PAI‐1 and CHD from the literature up until July 2016. This is a forest plot depicting the result of the meta‐analysis based on previous publications for observations of plasminogen activator inhibitor type 1 (PAI‐1) and coronary heart disease (CHD) association. Odds ratio (OR) with 95% CI is the OR of CHD comparing the highest PAI‐1 quantile to lowest PAI‐1 quantile, which is also represented as a point with bar in the plot. The diamond represents the meta‐analysis result using a random effects model. A, PAI‐1‐CHD associations adjusted for age, sex, and ethnic group in each study. B, PAI‐1‐CHD association in models adjusted for multiple CHD risk factors.
Figure 3
Figure 3
Scatter plots for genetic associations with CHD against genetic associations with PAI‐1. This shows scatter plots of genetic associations with coronary heart disease (CHD) against genetic associations with plasminogen activator inhibitor type 1 (PAI‐1). Lines in the horizontal and vertical directions represent 95% CI of genetic associations with PAI‐1 and CHD, respectively. The SNP marked in red (rs2227631) located in SERPINE1 is the SNP with the lowest P‐value reported in the genome‐wide association study of PAI‐1.28 A, Scatter plot of 4 correlated SNPs selected in the SERPINE1 locus as instrumental variable. B, Scatter plot of 4 independent SNPs selected from multiple loci as instrumental variable. SNP indicates single nucleotide polymorphism.
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